kiss1-protein--human and Carcinoma--Non-Small-Cell-Lung

Non-Small Cell Lung Cancer (NSCLC) remains an aggressive and fatal disease with low responsiveness to chemotherapy, frequent drug resistance development and metastatic behavior. Platinum-based therapy is the standard of care for NSCLC with limited benefits. Since epigenetic alterations have been implicated in the aggressive behavior of lung cancer, the purpose of the present study was to examine the capability of the pan-histone deacetylase inhibitor SAHA and of ST3595, a novel hydroxamate-based compound, to interfere with the proliferative and invasive potential of NSCLC cells. We used two NSCLC cell lines (H460 and A549) and the cisplatin-resistant variants (H460/Pt and A549/Pt), to mimic a frequent clinical condition. The resistant models exhibited increased invasive properties as compared to parental cells, features associated with a wide modulation of the level of angiogenesis- and invasion-related factors in the cell conditioned media. The levels of urokinase-type plasminogen activator, IL-8, and macrophage migration inhibitory factor were increased in the conditioned media from both H460/Pt and A549/Pt cells. SAHA and ST3595 induced a strong inhibition of cell invasive properties, which was more marked after ST3595 exposure. Both HDAC inhibitors up-regulated the metastasis suppressor KiSS1 at the mRNA level. Forced expression of KiSS1 significantly decreased the invasive capability of drug-resistant cells. ST3595 displayed an anti-metastatic effect in tumors associated with decreased of phosphorylation of Src. Our data indicate that HDAC inhibitors are effective in NSCLC cell systems. The ability of ST3595 to counteract the invasive potential of resistant cells through mechanisms involving KiSS1 is an interesting novel finding.

Topics: Animals; Antineoplastic Agents; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Cisplatin; Drug Resistance, Neoplasm; Enzyme-Linked Immunosorbent Assay; Female; Histone Deacetylase Inhibitors; Humans; Kisspeptins; Lung Neoplasms; Mice; Mice, Nude; Phenotype

Lung cancer is the most commonly diagnosed cancer worldwide. Loss of KISS1 expression has been associated with progression and poor prognosis of various cancers, however, the precise role of KISS1 expression in non-small cell lung cancer (NSCLC) is not well defined. KISS1 receptor (KISS1R, also named GPR54) coupled to KISS1, has been shown to play a pivotal role in suppressing cancer metastasis. In this study, 56 NSCLC specimens were divided into stage IIIB (locally advanced) and stage IV (metastatic). The mRNA and protein levels of KISS1 and KISS1R in cancer tissues were found to be lower compared to that in normal tissues using RT-PCR and western blot analysis, respectively. In addition, the expression of both KISS1 and KISS1R in stage IV NSCLC was lower compared to that in stage IIIB stage NSCLC. The cumulative survival rate of the patients with KISS1 or KISS1R expression was significantly higher compared to that without expression. KISS1 or KISS1R expression in NSCLC can be used to indicate favorable prognosis for disease outcome. Metastin, the product of the KISS1 gene, was lower in the serum of patients with stage IV NSCLC compared to that in stage IIIB NSCLC.

Topics: Carcinoma, Non-Small-Cell Lung; Female; Gene Expression Regulation, Neoplastic; Genes, Tumor Suppressor; Humans; Kaplan-Meier Estimate; Kisspeptins; Lung Neoplasms; Male; Middle Aged; Neoplasm Metastasis; Neoplasm Staging; Proportional Hazards Models; Receptors, G-Protein-Coupled; Receptors, Kisspeptin-1; Survival Rate; Tumor Suppressor Proteins

In recent years, many studies have revealed the prognosis in patients with non-small cell lung cancer (NSCLC). In general, some clinic-pathological parameters have been related with prognosis. The aim of this study is to detect the relationship among lymphatic vessel density (LVD), microvessel density (MVD), expression of carcinoembryonic antigen (CEA) mRNA, metastasis suppressor genes (KAI1 and Kiss-1), and the prognosis of NSCLC patients.. Blood samples were collected from 57 cases of NSCLC. The transcription of CEA mRNA was detected via nested reverse transcriptase-polymerase chain reaction and micro-fluid chip. Immunohistochemistry was performed to detect the expression of LVD, MVD, KAI1 and Kiss-1 in the patients. All follow-up data were collected and analyzed.. The overall five-year survival rate was 18%, and the median survival was 34 months. TNM stage, lymph node metastasis, and expression of MVD, LVD, CEA mRNA and Kiss-1 were factors to survival, as determined via single survival analysis. Multivariate analysis demonstrated that TNM stage, lymph node metastasis, and expression of CEA mRNA were independent prognostic factors for NSCLC patients.. The expression of MVD, LVD, Kiss-1 and CEA mRNA is related to the prognosis of NSCLC.

Topics: Carcinoembryonic Antigen; Carcinoma, Non-Small-Cell Lung; Gene Expression Regulation, Neoplastic; Kangai-1 Protein; Kisspeptins; Lung Neoplasms; Lymphatic Vessels; Microvessels; Prognosis; RNA, Messenger

Metastin, the product of the KISS-1 gene, seems to represent a strong suppressant of metastasis for some types of cancer. The aim of this study is to explore whether circulating levels of metastin could be used as a marker for the metastatic potential of non-small cell lung cancer (NSCLC) as well as a diagnostic marker in NSCLC patients. The possible correlation between metastin and leptin circulating levels was also evaluated. Fasting serum levels of metastin and leptin were determined in 96 NSCLC patients at diagnosis (76 with metastatic disease and 21 with locally advanced disease) and 49 healthy volunteers using commercial available ELISA. Serum metastin levels presented no differences between NSCLC patients and healthy volunteers (1.18 ± 0.98 vs. 1.17 ± 0.39 ng/ml, P = 0.979) as well as between patients with metastatic and locally advanced disease (1.17 ± 1.05 vs. 1.21 ± 0.64 ng/ml, P = 0.872). There was no statistically significant correlation between circulating metastin and leptin levels in NSCLC patients and patients with locally advanced and metastatic disease. This study shows a lack of direct involvement of metastin in the diagnosis and metastatic potential of NSCLC.

Topics: Biomarkers, Tumor; Carcinoma, Non-Small-Cell Lung; Enzyme-Linked Immunosorbent Assay; Female; Humans; Kisspeptins; Leptin; Lung Neoplasms; Male; Middle Aged; Neoplasm Invasiveness; Neoplasm Staging; Tumor Suppressor Proteins

KISS1 and matrix metalloproteinase-9 (MMP-9) may play important roles as metastasis suppressor and metastasis promoter genes, respectively, in a variety of malignancies. However, there is little information about their possible roles in non-small cell lung cancer (NSCLC). The goals of this study were to determine the mRNA and protein expressions of KISS1 and MMP-9 in NSCLC and their relations to metastasis and prognosis. The mRNA and protein expressions of KISS1 and of MMP-9 protein were detected by in situ hybridization and immunohistochemistry respectively in 85 cases of NSCLC, and their matched lymph node metastases. Expressions of KISS1 mRNA and protein were significantly higher in low TNM stages of NSCLC (I-II) compared to more advanced stages (III-IV) (p<0.05). Moreover, in advanced TNM stages, cases without metastasis had higher KISS1 gene expression compared to those with lymph node metastasis (p<0.05). In contrast, MMP-9 expression was higher in stage III-IV NSCLC cases compared to stage I-II tumors (p<0.05) and higher in NSCLC cases with metastasis than those without metastasis (p<0.05). There was negative correction between KISS1 and MMP-9 protein expression (p<0.01). The 5-year survival rate in cases with higher KISS1 protein expression was significantly higher than in those with low expression (20.9 vs. 2.4%, p<0.01). However, the 5-year survival rate of patients with high MMP-9 protein expression were lower than those with low expression (19 vs. 4.7%, p<0.05). Our data suggest that KISS1 and MMP-9 may serve as potential prognostic and therapeutic markers in lung cancer.

Topics: Adult; Aged; Aged, 80 and over; Carcinoma, Non-Small-Cell Lung; Female; Humans; Immunohistochemistry; In Situ Hybridization; Kisspeptins; Lung Neoplasms; Lymphatic Metastasis; Male; Matrix Metalloproteinase 9; Middle Aged; Neoplasm Staging; RNA, Messenger; Survival Rate; Tumor Suppressor Proteins